Efficacy and safety of fosaprepitant for the prevention of nausea and emesis during 5 weeks of chemoradiotherapy for cervical cancer (the GAND-emesis study): a multinational, randomised, placebo-controlled, double-blind, phase 3 trial.

BACKGROUND: The role of the neurokinin-1 (NK-1) receptor antagonists in the prevention of radiation-induced nausea and vomiting has not been established. The purpose of the GAND-emesis study was to investigate the efficacy and safety of fosaprepitant in combination with palonosetron and dexamethasone in the prevention of nausea and vomiting during 5 weeks of fractionated radiotherapy and concomitant weekly cisplatin in patients with cervical cancer. METHODS: This investigator initiated, multinational, randomised, double-blind, placebo-controlled phase 3 trial, included women with cervical cancer scheduled to receive fractionated radiotherapy and weekly cisplatin 40 mg/m(2) for 5 weeks. Patients had to be naive to chemotherapy and radiotherapy. Patients were randomly assigned to receive either single doses of fosaprepitant 150 mg intravenously or placebo (saline) in combination with palonosetron 0·25 mg intravenously and dexamethasone 16 mg orally before cisplatin administration. Randomisation was done by the unmasked pharmacist, who used a list of six numbers (a block) provided in a sealed envelope. A web-based randomisation number generator was used to generate the full list of randomisation numbers that was split up in blocks of six numbers. All patients received oral dexamethasone 8 mg twice a day on day 2, 4 mg twice a day on day 3, and 4 mg once on day 4. The treatment was repeated for 5 weeks. The primary endpoint was the proportion of patients with sustained no emesis after 5 weeks of treatment. The modified intention-to-treat population (all patients who received study medication) was used for the statistical analyses. The study was registered with ClinicalTrials.gov, number NCT01074697. FINDINGS: Between June 15, 2010, and March 8, 2015, 246 patients from four countries consented to the study and were randomly assigned. Of these, 234 patients were eligible, having received study medication (118 received fosaprepitant, 116 received placebo). The proportion of patients with sustained no emesis at 5 weeks (competing risk analysis) was 48·7% (95% CI 25·2-72·2) for the placebo group compared with 65·7% (42·2-89·2) of patients for the fosaprepitant group. There was a significantly lower cumulative risk of emesis in the fosaprepitant group compared with the placebo group (subhazard ratio 0·58 [95% CI 0·39-0·87]; p=0·008). Treatments were generally well tolerated with few grade 3 adverse events none of which were related to the study treatment; the most common grade 3 adverse event during the 5 weeks of treatment was diarrhoea (11 [9%] of 118 patients in the fosaprepitant group vs six [5%] of 116 patients in the placebo group). There was only one report of a grade 4 adverse event (neutropenia), in the fosaprepitant group. No deaths were recorded in either group. INTERPRETATION: To our knowledge, this is the first study to investigate safety and efficacy of a NK-1 receptor antagonist during 5 weeks of radiotherapy and concomitant weekly cisplatin. Patients receiving fosaprepitant in addition to palonosetron and dexamethasone were less likely to experience emesis and nausea compared with those receiving palonosetron and dexamethasone alone. Both treatments were safe and well tolerated. Further investigations in other radiotherapy settings are warranted. FUNDING: Private and hospital or university funding, unrestricted grants from Biovitrum and Helsinn Healthcare SA.

Significance of age and comorbidity on treatment modality, treatment adherence, and prognosis in elderly ovarian cancer patients.

BACKGROUND: Age is associated with poor prognosis in ovarian cancer patients. Reasons could be increased comorbidity, more advanced stage, or nonoptimal surgery or chemotherapy. Objectives of this study were to evaluate the significance of comorbidity and age ≥70 years on receiving cytoreductive surgery, standard combination chemotherapy (TC), adherence to TC treatment, and prognosis. METHODS: A retrospective cohort study of all women registered in a nation-wide database with ovarian or peritoneal cancer in 2005-2006. Logistic regression was employed for determining the predictive value of age and comorbidity (ASA score) on receiving cytoreductive surgery and TC, and on adhering to TC. Kaplan-Meier method and Cox proportional hazards analysis were employed for survival analyses. RESULTS: Of 961 patients, 348 (36.2%) were elderly. Age ≥70 years was independently predictive of not receiving surgery, OR 0.2(95% CI 0.1-0.5) and TC treatment, OR 0.03 (95% CI 0.01-0.1). Comorbidity was also independently predictive of not receiving standard treatment: OR for receiving surgery with ASA score of ≥3 was 0.2 (95% CI 0.1-0.5), and for receiving TC it was 0.03 (95% CI 0.01-0.1). Overall, age ≥70 was a poor prognostic factor in OS and PFS, but the effect of age ceased after 16 months. Comorbidity was a poor prognostic factor throughout the study period but with time-varying effect. For patients treated with TC, age was not a prognostic factor, whereas ASA score ≥3 was. CONCLUSION: Elderly patients and patients with comorbidity less often receive optimal surgical and medical treatment. For those receiving optimal treatment, age ≥70 is not an independent poor prognostic factor, whereas severe comorbidity is.

Stereotactic body radiotherapy for medically inoperable patients with stage I non-small cell lung cancer - a first report of toxicity related to COPD/CVD in a non-randomized prospective phase II study.

BACKGROUND AND AIMS: In a retrospective study using stereotactic body radiotherapy (SBRT) in medically inoperable patients with stage I NSCLC we previously reported a local control rate of 88% utilizing a median dose of 15Gyx3. This report records the toxicity encountered in a prospective phase II trial, and its relation to coexisting chronic obstructive pulmonary disease (COPD) and cardio vascular disease (CVD). MATERIAL AND METHODS: Sixty patients were entered in the study between August 2003 and September 2005. Fifty-seven patients (T1 65%, T2 35%) with a median age of 75 years (59-87 years) were evaluable. The baseline mean FEV1% was 64% and median Karnofsky index was 80. A total dose of 45Gy was delivered in three fractions at the 67% isodose of the PTV. Clinical, pulmonary and radiological evaluations were made at 6 weeks, 3, 6, 9, 12, 18, and 36 months post-SBRT. Toxicity was graded according to CTC v2.0 and performance status was graded according to the Karnofsky scale. RESULTS: At a median follow-up of 23 months, 2 patients had relapsed locally. No grade 4 or 5 toxicity was reported. Grade 3 toxicity was seen in 12 patients (21%). There was no significant decline of FEV1% during follow-up. Low grade pneumonitis developed to the same extent in the CVD 3/17 (18%) and COPD 7/40 (18%) groups. The incidence of fibrosis was 9/17 (53%) and pleural effusions was 8/17 (47%) in the CVD group compared with 13/40 (33%) and 5/40 (13%) in the COPD group. CONCLUSION: SBRT for stage I NSCLC patients who are medically inoperable because of COPD and CVD results in a favourable local control rate with a low incidence of grade 3 and no grade 4 or 5 toxicity.

Simple DVH parameter addition as compared to deformable registration for bladder dose accumulation in cervix cancer brachytherapy.

BACKGROUND AND PURPOSE: Variations in organ position, shape, and volume cause uncertainties in dose assessment for brachytherapy (BT) in cervix cancer. The purpose of this study was to evaluate uncertainties associated with bladder dose accumulation based on DVH parameter addition (previously called "the worst case assumption") in fractionated BT. MATERIALS AND METHODS: Forty-seven patients treated for locally advanced cervical cancer were included. All patients received EBRT combined with two individually planned 3D image-guided adaptive BT fractions. D(2cm(3)) and D(0.1cm(3)) were estimated by DVH parameter addition and compared to dose accumulations based on an in-house developed biomechanical deformable image registration (DIR) algorithm. RESULTS: DIR-based DVH analysis was possible in 42/47 patients. DVH parameter addition resulted in mean dose deviations relative to DIR of 0.4±0.3 Gy(αß3) (1.5±1.8%) and 1.9±1.6 Gy(αß3) (5.2±4.2%) for D(2cm(3)) and D(0.1cm(3)), respectively. Dose deviations greater than 5% occurred in 2% and 38% of the patients for D(2cm(3)) and D(0.1cm(3)), respectively. Visual inspection of the dose distributions showed that hotspots were located in the same region of the bladder during both BT fractions for the majority of patients. CONCLUSION: DVH parameter addition provides a good estimate for D(2cm(3)), whereas D(0.1cm(3)) is less robust to this approximation.

Clinical feasibility of combined intracavitary/interstitial brachytherapy in locally advanced cervical cancer employing MRI with a tandem/ring applicator in situ and virtual preplanning of the interstitial component.

PURPOSE: To investigate the reproducibility of virtually planned needles, changes in DVH parameters and clinical feasibility of combined intracavitary/interstitial (IC/IS) pulsed dose rate brachytherapy (PDR-BT) for locally advanced cervical cancer based on 3D MRI preplanning. MATERIAL AND METHODS: Fifty-eight consecutively patients accrued in the EMBRACE study were included. Treatment was initiated with external beam radiotherapy and cisplatin. Three BT implants and MRI with the applicator in situ were performed in all patients, i.e. week 5 (BT0), week 6 (BT1) and week 7 (BT2) of the treatment. BT0 was only used for preplanning of subsequent implantations, whereas BT1 and BT2 comprised 2 equal sized fractions of PDR BT. RESULTS: Based on BT0, 24 patients (41%) were selected for a combined IC/IS implant at BT1 and BT2. Patients treated with IC/IS BT had significantly larger tumours compared with patients treated with IC BT only (p<0.03). Additional time in general anaesthesia for the IC/IS component was on average 16 min. The number of preplanned virtual needles was 5.3±2.7 compared to 5.3±2.9 and 5.4±3.0 needles implanted at BT1 and BT2, respectively (p=0.72). Planned needle implantation depth was 33±15 mm compared to 30±10 mm at BT1 and 29±11 mm at BT2 (p=0.04). In the 24 patients selected for IC/IS BT both the virtual IC/IS plan (BT0) and the actually delivered plan (BT1+BT2) significantly increased D90 and D100 for HR CTV (p<0.01) and reduced D2cc for sigmoid (p<0.01) and bowel (p=0.04) compared to the optimised IC preplan (BT0). IC/IS BT was only associated with minor morbidity, which was resolved at a 3-month follow up. CONCLUSION: Combined IC/IS BT based on full 3D MRI preplanning is clinically feasible. The virtual preplanned needle positions are reproducible at subsequent BT applications leading to significantly improved DVH parameters and a clinically feasible and fast implant procedure.

Co-morbidity index predicts for mortality after stereotactic body radiotherapy for medically inoperable early-stage non-small cell lung cancer.

PURPOSE: To determine the prognostic role of co-morbidity in medically inoperable early-stage non-small cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT). METHODS AND MATERIALS: Between 2000 and 2007, 88 consecutive early-stage medically inoperable NSCLC patients were treated by linac-based SBRT. The dose was either 45 Gy or 67.5 Gy in three fractions prescribed to the isocenter. Baseline co-morbidities were retrospectively retrieved by consultation of a formal electronic registry of diagnoses as well as patients' charts. The age-adjusted Charlson Co-morbidity Index (CCI) was scored for each patient and subjected to univariate and multivariate analysis. RESULTS: With a median follow-up of 44 months, the actuarial local control rate at 4 years was 89% while the median overall survival was 22 months. The median age-adjusted CCI score was 5. The age-adjusted CCI was a significant predictor of overall survival on both univariate (p=0.002) and multivariate analysis (p=0.011). Patients with an age-adjusted CCI score of 3 or less had a median survival of 41 months versus only 11 months for those scoring 6 or more. CONCLUSION: The number and seriousness of co-morbidities predict overall survival in medically inoperable early-stage NSCLC treated with SBRT. Because the determination of medical operability is frequently based on both objective measures and subjective clinical judgment, it is recommended that co-morbidity be formally indexed in all studies examining the outcomes of SBRT.

Outcome in a prospective phase II trial of medically inoperable stage I non-small-cell lung cancer patients treated with stereotactic body radiotherapy.

PURPOSE: The impact of stereotactic body radiotherapy (SBRT) on 3-year progression-free survival of medically inoperable patients with stage I non-small-cell lung cancer (NSCLC) was analyzed in a prospective phase II study. PATIENTS AND METHODS: Fifty-seven patients with T1NOMO (70%) and T2N0M0 (30%) were included between August 2003 and September 2005 at seven different centers in Sweden, Norway, and Denmark and observed up to 36 months. SBRT was delivered with 15 Gy times three at the 67% isodose of the planning target volume. RESULTS: Progression-free survival at 3 years was 52%. Overall- and cancer-specific survival at 1, 2, and 3 years was 86%, 65%, 60%, and 93%, 88%, 88%, respectively. There was no statistically significant difference in survival between patients with T1 or T2 tumors. At a median follow-up of 35 months (range, 4 to 47 months), 27 patients (47%) were deceased, seven as a result of lung cancer and 20 as a result of concurrent disease. Kaplan-Meier estimated local control at 3 years was 92%. Local relapse was observed in four patients (7%). Regional relapse was observed in three patients (5%). Nine patients (16%) developed distant metastases. The estimated risk of all failure (local, regional, or distant metastases) was increased in patients with T2 (41%) compared with those with T1 (18%) tumors (P = .027). CONCLUSION: With a 3-year local tumor control rate higher than 90% with limited toxicity, SBRT emerges as state-of-the-art treatment for medically inoperable stage I NSCLC and may even challenge surgery in operable instances.

[The psychosocial work environment of junior physicians in Danish oncology departments. A questionnaire-based cross-sectional study]. / Psykisk arbejdsmiljø blandt yngre laeger på onkologiske afdelinger. Et spørgeskemabaseret tvaersnitsstudie.

INTRODUCTION: Employees in departments of oncology in Denmark are faced with the public's expectations of increased productivity and quality. Understaffing is a serious obstacle to the fulfillment of these expectations. In 2006, the psychosocial work environment was examined among junior physicians working in Danish departments of oncology. MATERIALS AND METHODS: The Department of Occupational Medicine at Aarhus University Hospital conducted a psychosocial work environment-questionnaire among 121 junior physicians employed at six departments of oncology in May 2006. Participation was voluntary and anonymous. RESULTS: The response rate was 87%. Meaningfulness and developing potentiality of employment as well as involvement in the workplace were rated higher by the junior physicians than by average Danish workers. However, as for quantitative and emotional work demands and the experience of influence and predictability at work, the assessment of the psychosocial work environment is significantly poorer. There is considerable inter-departmental variation. The junior physicians call for more staff, a higher prioritization of education, and an improved psychosocial work environment. CONCLUSION: Despite meaningfulness and developing potentiality of employment, the psychosocial work environment of junior physicians in Danish departments of oncology is perceived as significantly poorer than that of average Danish workers. This study provides a basis for developing strategies to improve working conditions and facilitate the recruitment and maintenance of junior physicians in clinical oncology.

Aggravation of dyspnea in stage I non-small cell lung cancer patients following stereotactic body radiotherapy: Is there a dose-volume dependency?

In SBRT for NSCLC, highly potent radiation doses are delivered to patients with frequent pre-irradiatory compromise of pulmonary function. For the risk of pulmonary toxicity to be minimized during SBRT planning, data on its dose-volume dependency is needed. In the present study, we analyse the association of dose-volume histogram parameters with changes in dyspnea. The study concerns 28 medically inoperable stage I NSCLC patients that received SBRT at our department between 2000 and 2003. A central dose of 45 Gy/3 fractions was delivered in 5-8 days. WHO toxicity scoring of dyspnea was prospectively performed at baseline and during a 6-month follow-up post-SBRT. DVH parameters for pulmonary tissue were retrieved from the 3-D dose distributions. Aggravated dyspnea was registered in 11 patients (40%). We found no association between DVH parameters and changes in dyspnea. Nor did we find any consistent temporal variations of dyspnea after SBRT. We identified COPD as the factor showing the closest association with aggravation of dyspnea. The observed aggravation of dyspnea following SBRT reflects habitual exacerbations of COPD rather than treatment-related toxicity. Concern about pulmonary toxicity should not be prohibitive for future studies targeting limitations to dose and volume.

Factors important for efficacy of stereotactic body radiotherapy of medically inoperable stage I lung cancer. A retrospective analysis of patients treated in the Nordic countries.

We reviewed results of SBRT treatment of 138 patients with medically inoperable stage I NSCLC treated during 1996-2003 at five different centres in Sweden and Denmark. Mean age was 74 years (range 56-90) with 69 men and 72 women. SBRT was delivered using a 3D conformal multifield technique and a stereotactic body frame. Doses delivered were 30-48 Gy (65% isodose at the periphery of planning target volume, PTV) in 2-4 fractions. Equivalent dose in 2 Gy fractions (EQD2) was in the range of 50-100 Gy. Mean gross tumour volume (GTV) was 39 cm3 (2-436), and planning target volume was 101 cm3 (11-719). Overall response rate (CR, PR) was 61% (84/138). SD was noted in 36% (50/138). During a median follow-up period of 33 months (1-107), 16 (12%) local failures occurred, ten of which also included distant metastases. Local failure was associated with tumour size, target definition and central or pleura proximity. Distant metastases occurred in 25% (35/138) of the patients. Ninety-one (65%) patients died during follow-up of which 55 patients (60%) died of other causes than lung cancer. Three- and 5-year overall survival was 52 and 26% respectively. Lung cancer specific 3- and 5-year overall survival was 66 and 40% respectively. Fifty nine percent (83/138) of the patients had no side effects. Fourteen patients experienced grade 3-4 toxicity according to radiation therapy oncology group (RTOG). EQD2 (> v.s.<55.6 Gy) showed a statistically significant benefit survival for the higher doses. SBRT for stage I NSCLC results in favourable local control not inferior to fractionated RT and with acceptable toxicity.